Abstract:Cucurbit[7]uril (CB[7]) is a molecular container that may form host–guest complexes with platinum(II) anticancer drugs and modulate their efficacy and safety. In this paper, we report our studies of the effect of CB[7]–oxaliplatin complex and the mixture of CB[7] and carboplatin (1:1) on viability and proliferation of a primary cell culture (peripheral blood mononuclear cells), two tumor cell lines (B16 and K562) and their activity in the animal model of melanoma. At the same time, we studied the impact of pla… Show more
“…On the basis of these observations, we propose to further characterize different fibril morphologies obtained via the addition of CB[7] for ENF and, potentially, other peptides. This would be of particular interest since different fibril morphologies have been reported to exhibit distinct physicochemical properties and stabilities that have been exploited for drug delivery and biotechnological applications. , For therapeutic applications, we are not aware of detailed toxicological studies on CB[7], although we note that it has been used as an excipient for anticancer agents in animal models, without evidence of direct toxic effects . Further, its use in reducing the toxicity of paraquat and neurotoxic drugs has been reported, suggesting potential for in vivo compatibility.…”
Fibrillation is a challenge commonly encountered in the
formulation
and development of therapeutic peptides. Cucurbit[7]urils (CB[7]),
a group of water soluble macrocycles, have been reported to suppress
fibrillation in insulin and human calcitonin through association with
Phe and Tyr residues which drive fibril formation. Here, we report
the effect of CB[7] on the fibrillation behavior of the HIV fusion
inhibitor enfuvirtide (ENF) that contains N-terminal Tyr and C-terminal
Phe residues. Thioflavin T fluorescence, CD spectroscopy, and transmission
electron microscopy were used to monitor fibrillation behavior. Fibrillation
onset showed a strong pH dependency, with pH 6.5 identified as the
condition most suitable to monitor the effects of CB[7]. Binding of
CB[7] to wild-type ENF was measured by isothermal titration calorimetry
and was consistent with a single site (K
a = 2.4 × 105 M–1). A weaker interaction
(K
a = 2.8 × 103 M–1) was observed for an ENF mutant with the C-terminal
Phe substituted for Ala (ENFm), suggesting that Phe was the specific
site for CB[7] recognition. The onset of ENF fibrillation onset was
delayed, rather than fully suppressed, in the presence of CB[7]. The
ENFm mutant showed a greater delay in fibrillation onset but with
no observable effect on fibrillation kinetics in the presence of CB[7].
Interestingly, ENF/CB[7] and ENFm fibrils exhibited comparable morphologies,
differing from those observed for ENF alone. The results indicate
that CB[7] is capable of modulating fibrillation onset and the resulting
ENF fibrils by specifically binding to the C-terminal Phe residue.
The work reinforces the potential of CB[7] as an inhibitor of fibrillation
and highlights its role in determining fibril morphologies.
“…On the basis of these observations, we propose to further characterize different fibril morphologies obtained via the addition of CB[7] for ENF and, potentially, other peptides. This would be of particular interest since different fibril morphologies have been reported to exhibit distinct physicochemical properties and stabilities that have been exploited for drug delivery and biotechnological applications. , For therapeutic applications, we are not aware of detailed toxicological studies on CB[7], although we note that it has been used as an excipient for anticancer agents in animal models, without evidence of direct toxic effects . Further, its use in reducing the toxicity of paraquat and neurotoxic drugs has been reported, suggesting potential for in vivo compatibility.…”
Fibrillation is a challenge commonly encountered in the
formulation
and development of therapeutic peptides. Cucurbit[7]urils (CB[7]),
a group of water soluble macrocycles, have been reported to suppress
fibrillation in insulin and human calcitonin through association with
Phe and Tyr residues which drive fibril formation. Here, we report
the effect of CB[7] on the fibrillation behavior of the HIV fusion
inhibitor enfuvirtide (ENF) that contains N-terminal Tyr and C-terminal
Phe residues. Thioflavin T fluorescence, CD spectroscopy, and transmission
electron microscopy were used to monitor fibrillation behavior. Fibrillation
onset showed a strong pH dependency, with pH 6.5 identified as the
condition most suitable to monitor the effects of CB[7]. Binding of
CB[7] to wild-type ENF was measured by isothermal titration calorimetry
and was consistent with a single site (K
a = 2.4 × 105 M–1). A weaker interaction
(K
a = 2.8 × 103 M–1) was observed for an ENF mutant with the C-terminal
Phe substituted for Ala (ENFm), suggesting that Phe was the specific
site for CB[7] recognition. The onset of ENF fibrillation onset was
delayed, rather than fully suppressed, in the presence of CB[7]. The
ENFm mutant showed a greater delay in fibrillation onset but with
no observable effect on fibrillation kinetics in the presence of CB[7].
Interestingly, ENF/CB[7] and ENFm fibrils exhibited comparable morphologies,
differing from those observed for ENF alone. The results indicate
that CB[7] is capable of modulating fibrillation onset and the resulting
ENF fibrils by specifically binding to the C-terminal Phe residue.
The work reinforces the potential of CB[7] as an inhibitor of fibrillation
and highlights its role in determining fibril morphologies.
“…For instance, CB7 improved the antitumor activity of carboplatin and oxaliplatin, platinumbased anticancer drugs. 45 The anticancer activity of Ps against HT-29 and HCT-116 colon cancer cells has been previously established. 46 Several mechanisms have been suggested.…”
Nowdays, natural compounds are extensively studied for the prevention and treatment of various types of cancer due to their remarkable healing properties.
“…The role of CB8 in triggering cellular internalization to white blood cancer cells was investigated. While it is not uncommon to see such systems at work in small organic molecules that change their cellular uptake under the influence of CB macrocycles, 22 using such systems for extended networked structures such as the present CB8‐based alginate hydrogels (VGCB8ALG) is purely academic and should unfold more information.…”
The cellular uptake of drug carriers to the cytosol of a specific cell remains challenging, and a non‐classical supramolecular strategy is motivated. Here, we select a model host–guest complex in which a diamino‐viologen (1,1′‐bis(4‐aminophenyl)‐[4,4′‐bipyridine]−1,1′‐diium dichloride [VG]) fluorescent tag was engulfed by cucurbit[8]uril (CB8) and covalently linked to alginate polysaccharides (alginic acid [ALG]) as the modified drug vehicle. When adsorbed on the ALG surface, the encapsulation of VG was first confirmed utilizing Fourier transform infrared and nuclear magnetic resonance spectroscopic methods. Solid optical measurements (diffuse reflectance spectroscopy, photoluminescence, and time‐resolved photoluminescence) revealed emissive materials at around 650 nm and that CB8 enhanced the rigidity of the modified hydrogel. The molar composition of 2:1 for the complexation of VG to CB8 on the alginate surface and the thermal stabilities were also confirmed using thermogravimetric analysis and differential scanning calorimetry techniques. CB8 induced a dramatic decrease in the average size of the VGALG polysaccharides from 485 to 165 nm and a turnover in their charge from –19.8 to +14.4 mV. Flow cytometry with inhibitors of various endocytosis pathways was employed to track the cellular uptake across different blood cell types: human T‐cell leukemia 1301 and peripheral blood mononuclear cells. Noticeably, complexation of VG with the CB8 host on top of the sugar platform dramatically enhanced the internalization into 1301 cells (viz. from 1% to 99%) at a concentration of 1.8 mg/mL via caveolae‐mediated endocytosis because of the size reduction, turnover in the charge from negative to positive, and rigidity induction. These observations reveal a more profound understanding of the macrocyclic effects on drug delivery.
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